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M Lanotte

Publications and source records attributed to M Lanotte.

At least 55 records · Page 3Linked to original sources
PubMed1998

A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels.

cAMP-dependent signal transduction co-operates with retinoids to induce acute promyelocytic leukaemia (APL) cell maturation. The rationale of this work was to determine whether signal cross-talk could be used to decrease the pharmacological doses of retinoids in the treatment of APL. When only the basal level of adenylate-cyclase (AC) activity is present in NB4 cells, up to 1 microM concentration of all-trans retinoic acid (RA) is required for full maturation (100%). In these conditions, with only 10 nM RA less than 20% of cells will differentiate. Although the use of membrane receptor agonists to activate AC has been proved to synergize with RA treatment, these agents were never as potent as cell permeant cAMP analogues. Analogues have disadvantages since cleavage by serum and cellular phosphodiesterases generates metabolites which interfere in cellular response. In the present study, we observed cell maturation by engrafting an autonomous Bordetella pertussis AC which steadily delivers natural cAMP into the cell. The enzyme alone had no effect on cell maturation. Importantly, cell maturation was increased in a dose-dependent manner when the bacterial AC (1 ng/ml to 1 microg/ml) was used to potentiate the effects of low doses RA (10 nM). More than 50% of cells matured with only 10 nM of RA and 200 ng/ml of B. pertussis AC. The maturation response was significantly increased when lower amounts of enzyme were repetitively added to the culture to compensate for enzymatic decay. These results indicate that a sustained AC activity enhanced cell maturation. We were able to reduce to 3 nM the RA requirement, provided that a minimal amount (20 ng/ml) of B. pertussis AC was added every 12 h in culture. Membrane signalling maintaining high the level of cAMP substantially improved the efficacy of APL cell maturation by retinoids. Therefore, therapeutic benefits are expected by lowering the concentration of RA towards physiological (nanomolar) levels, thus reducing the side-effects of the drug. cAMP-elevating drugs that act on a post-cyclase target (cyclic-nucleotide phosphodiesterases) or cell-targeted drug carriers (cAMP and RA loaded liposomes) should be evaluated as maturation therapies combining the activation of multiple signalling pathways.

Cyclic AMP↗
PubMed1998

Expression patterns of the JEM-1 gene in normal and tumor cells: ubiquity contrasting with a faint, but retinoid-induced, mRNA expression in promyelocytic NB4 cells.

The JEM-1 gene, recently identified in acute promyelocytic leukemia (APL) cells, codes for a novel nuclear factor (Duprez et al Oncogene 1997; 14: 1563-1570). JEM-1 is kept silent in the APL cell line NB4, but up-regulated (3 kb transcript) during cell maturation. Here, we show that retinoic acid (RA)-induced JEM-1 expression is biphasic (peaks at 6 h and 48 h) and associated with the later stages of maturation. Retinoids, which cooperates with cAMP to induce maturation, also cooperates with cAMP to up-regulate JEM-1, either in maturation-responsive NB4 cells or in NB4-R1 resistant subclones. APL patients showed a low, yet variable, level of JEM-1 mRNA in bone marrow. RA treatment induced an increase in the level of JEM-1 mRNA, as detected by a semi-quantitative PCR. This increase can result from both gene up-regulation or replacement of leukemia cells by differentiated ones. Analysis of JEM-1 expression patterns in normal and tumor cells revealed that JEM-1 expression was ubiquitous. Cell lines derived from monocytic and erythroid leukemias, expressed low and high amounts of JEM-1 mRNA, respectively. Using a JEM cDNA probe, distinct profiles of expression and different transcript sizes (4 kb, 3 kb and 2 kb) were also identified in tumour and normal non-hematopoietic tissues, while interestingly only the 3kb transcript was up-regulated in NB4 cells. This work identifies JEM-1 as a novel ubiquitous gene whose expression is low in APL cells, but can be restored by RA treatment, concomitant with cell maturation.

Adult↗
PubMed1997

The transcriptional repressor ICER and cAMP-induced programmed cell death.

The cAMP pathway plays a central role in the response to hormonal signals for cell proliferation, differentiation and apoptosis. In IPC-81 leukaemia cells, activation of the cAMP pathway by prostaglandin E1 treatment, or other cAMP-elevating agents, induces apoptosis within 4-6 h. Inhibition of mRNA or protein synthesis during the first 2 h of cAMP induction protects cells from apoptosis, suggesting a requirement for early gene expression. cAMP-dependent protein kinase phosphorylates a class of nuclear factors and thereby regulates the transcription of a specific set of genes. Here we show that CREM (cAMP Responsive Element Modulator) expression is induced rapidly upon prostaglandin E1 treatment of IPC-81 cells. The induced transcripts correspond to the early product ICER (Inducible cAMP Early Repressor). ICER expression remains elevated until the burst of cell death. Protein synthesis inhibitors which prevent cAMP-induced apoptosis also block de novo ICER synthesis. Transfected IPC-81 cell lines, constitutively expressing high level of ICER are resistant to cAMP-induced cell death. In these transfected cells, cAMP fails to upregulate the ICER transcripts demonstrating that ICER exerts strongly its repressor function on CRE-containing genes. That an early expression of ICER blocks apoptosis, suggests that gene repression by endogenous ICER in IPC-81 is insufficient or occurs too late to protect cells against death. ICER transfected cells rescued from cAMP-induced apoptosis are growth arrested. It shows for the first time that CREM activation directly participates to the decision of the cell to die. ICER, by sequentially repressing distinct sets of CRE-containing genes could modulate cell fate.

Alprostadil↗
PubMed1997

Cloning of a gene (RIG-G) associated with retinoic acid-induced differentiation of acute promyelocytic leukemia cells and representing a new member of a family of interferon-stimulated genes.

In a cell line (NB4) derived from a patient with acute promyelocytic leukemia, all-trans-retinoic acid (ATRA) and interferon (IFN) induce the expression of a novel gene we call RIG-G (for retinoic acid-induced gene G). This gene codes for a 58-kDa protein containing 490 amino acids with several potential sites for post-translational modification. In untreated NB4 cells, the expression of RIG-G is undetectable. ATRA treatment induces the transcriptional expression of RIG-G relatively late (12-24 hr) in a protein synthesis-dependent manner, whereas IFN-alpha induces its expression early (30 min to 3 hr). Database search has revealed a high-level homology between RIG-G and several IFN-stimulated genes in human (ISG54K, ISG56K, and IFN-inducible and retinoic acid-inducible 58K gene) and some other species, defining a well conserved gene family. The gene is composed of two exons and has been mapped by fluorescence in situ hybridization to chromosome 10q24, where two other human IFN-stimulated gene members are localized. A synergistic induction of RIG-G expression in NB4 cells by combined treatment with ATRA and IFNs suggests that a collaboration exists between their respective signaling pathways.

Amino Acid Sequence↗
PubMed1997

Altered sensitivity to retinoid-induced apoptosis associated with changes in the subcellular distribution of Bcl-2.

In the acute promyelocytic leukemia cell line NB4, Bcl-2 downregulation occurred as a late event of retinoid-induced differentiation. In the maturation-resistant NB4-R1 subclone, retinoids failed to downregulate Bcl-2 even in the situation of apoptosis massively induced by pan-agonists and RXR-selective agonists. We observed that NB4 and NB4-R1 cells differed with respect to the intracellular localization of Bcl-2 which showed a perinuclear localization in NB4-R1 cells, while Bax was broadly expressed in the cytoplasm and to only a minor extent in the perinuclear area. Therefore, the distinct intracellular localization of Bcl-2 and Bax was in general nonoverlapping. Bcl-2 remained massively expressed until cell disruption. Bax was not significantly upregulated in cells committed to death. However, Bax localization changed from a diffuse pattern to concentrate in few specific cytoplasmic area at a stage preceding the formation of apoptotic bodies. A human Bcl-2 transgene was transiently overexpressed in NB4-R1 cells which showed increased resistance to apoptosis induced by retinoids. Stably transfected clones of NB4-R1 cells showed an increased expression of Bcl-2 and a marked resistance to apoptosis. Interestingly, the overexpression of Bcl-2 restored a pattern of uniform Bcl-2 labeling in the cytoplasm and, remarkably, the colocalization of Bcl-2 with Bax. This work demonstrates that the ability of retinoid-induced cells to undergo apoptosis depends on the level of expression and the functional interaction between Bcl-2 and Bax.

Apoptosis↗
PubMed1997

JEM-1, a novel gene encoding a leucine-zipper nuclear factor upregulated during retinoid-induced maturation of NB4 promyelocytic leukaemia.

Retinoid-induced proliferation causing hyperleukocytosis is a severe complication of retinoid therapy in t(15;17) acute promyelocytic leukaemia. The molecular basis of this phenomenon is unknown. It is possible that the transiently enhanced cell proliferation results from RA-induction of growth regulatory genes. Using Differential Display of cDNAs from NB4 cells we have identified Jem, a novel gene transcript which is upregulated by retinoids during the early proliferative response in maturating cells but not in resistant cells. A 2.7 kb cDNA was cloned and sequenced. The open reading frame contains a 400 amino acid sequence corresponding to a novel 45 kDa basic protein (pI 8.9). The JEM DNA sequence is detected by FISH on human chromosome 1 at q24. The Jem peptide sequence shows a 'leucine-zipper' dimerisation motif with limited homology to Fos/Jun and ATF/CREB proteins and several putative phosphorylation sites. An atypical basic region may correspond to an unknown DNA-binding domain. The C-terminal end of Jem spans a long stretch featuring a PEST motif. After transfection into COS cells, the Jem protein shows a ponctuated nuclear localisation. We hypothesise that this novel nuclear factor may act as a transcription factor, or a coregulator, involved in either cell growth control and/or maturation.

Amino Acid Sequence↗
PubMed1997

Prolactin receptors in human meningiomas: characterization and biological role.

Sixty cerebral meningioma specimens obtained at surgery from 34 female and 26 male patients were examined for the presence of prolactin (PRL) receptors. These were compared with normal arachnoid tissue from which these tumours arise. PRL receptors were detected in 61.7% of meningiomas whereas no PRL binding was found in samples of normal arachnoid tissue. No relationship was found when sex or histological findings were compared with the presence of PRL receptors. Receptor-positive tumours had saturable and high-affinity (Kd, 4.8 +/- 0.5 ng/ml) receptors with hormonal specificity for human PRL (hPRL) resembling that of other target tissues of PRL in man. The biological role of these receptors was investigated in primary cell cultures derived from meningioma tissue characterized for PRL receptor. When human PRL was added to the culture medium, in doses ranging from 1 to 200 ng/ml, a dose-dependent stimulation of 3H-thymidine incorporation was observed only in PRL-receptor positive tumours. The PRL concentrations required to produce a half-maximal effect ranged from 11 to 20 ng/ml and were quite close to the dissociation constant (Kd) of binding of PRL to its receptors. PRL also caused an increase of cell number compared with control with a significant effect after 3 and 4 days of culture. In conclusion, these findings indicate that a large number of human meningiomas express specific and functional receptors for PRL which are involved in mediating its proliferative effects.

Adult↗
PubMed1996

RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid during the differentiation of acute promyelocytic leukemia cell.

In vivo all-trans-retinoic acid (ATRA), a differentiation inducer, is capable of causing clinical remission in about 90% of patients with acute promyelocytic leukemia (APL). The molecular basis for the differentiation of APL cells after treatment with ATRA remains obscure and may involve genes other than the known retinoid nuclear transcription factors. We report here the ATRA-induced gene expression in a cell line (NB4) derived from a patient with APL. By differential display-PCR, we isolated and characterized a novel gene (RIG-E) whose expression is up-regulated by ATRA. The gene is 4.0 kb long, consisting of four exons and three introns, and is localized on human chromosome region 8q24. The deduced amino acid sequence predicts a cell surface protein containing 20 amino acids at the N-terminal end corresponding to a signal peptide and an extracellular sequence containing 111 amino acids. The RIG-E coded protein shares some homology with CD59 and with a number of growth factor receptors. It shares high sequence homology with the murine LY-6 multigene family, whose members are small cysteine-rich proteins differentially expressed in several hematopoietic cell lines and appear to function in signal transduction. It seems that so far RIG-E is the closest human homolog of the LY-6 family. Expression of RIG-E is not restricted to myeloid differentiation, because it is also present in thymocytes and in a number of other tissues at different levels.

Amino Acid Sequence↗
PubMed1996

Differential changes of retinoid-X-receptor (RXR alpha) and its RAR alpha and PML-RAR alpha partners induced by retinoic acid and cAMP distinguish maturation sensitive and resistant t(15;17) promyelocytic leukemia NB4 cells.

The expression of retinoid receptors (RXRalpha, RARalpha and the chimeric form PML-RARalpha) was analysed both at the mRNA and protein level in the maturation sensitive NB4 and resistant NB4-R1 cell lines of t(15;17) promyelocytic leukemia (APL). All-trans RA and cAMP which show synergistic activity in inducing maturation of NB4 cells and maturation triggering of the RA 'primed' NB4-R1 resistant cells, distinctly modulate RXRalpha, RARalpha and PML-RARalpha mRNA. In the NB4 and NB4-R1 cells, RXRalpha mRNA was downregulated by RA, but only in RA-primed NB4-R1 cells a release from RXRalpha mRNA downregulation was obtained by cAMP treatment. RXRalpha protein (53 kDa) was decreased to the western-blot detection limit (97.5%) by RA in NB4 cells, but in NB4-R1 cells although it was frankly decreased (85%), the signal for RXRalpha protein remained very significant. More importantly, while cAMP slightly upregulated RXRalpha protein in RA-treated NB4 cells, it caused an increase of RXRalpha protein in RA-treated NB4-R1 cells bringing RXRalpha to the initial control level. RXRalpha partners in heterodimers (PML-RARalpha, RARalpha) were also analysed. In contrast to RXRalpha, RARalpha and PML-RARalpha mRNA were not modulated by RA and/or cAMP, while significant changes were observed at the protein levels. A putatively phosphorylated form of RARalpha (52 kDa) decreased during maturation of NB4 cells, but was unchanged in resistant NB4-R1 cells. Conversely, while PML-RARalpha remained stable during RA-induced NB4 maturation, RA treatment which failed to induce maturation of NB4-R1 cells significantly down-regulated the chimeric receptor (120 kDa). These differences most likely results from translational and post-translational regulation. This work reveals complex pattern of subtle changes at the protein level distinguishing RA-sensitive and RA-resistant cells. Our data show that the RA-cAMP synergistic effect on NB4 cell maturation and cooperation in triggering maturation of RA-primed NB4-R1 cells operate changes in the RXR/PML-RARalpha ratio which are both favouring RXRalpha. In both cell lines, variations of PML-RARalpha and RXRalpha may result in a decrease in the formation of the PML-RARalpha/RXRalpha heterodimers which are supposed involved in the block of maturation. This may prove crucial to embark cells on maturation.

Cell Cycle↗
PubMed1996

cAMP signalling is decisive for recovery of nuclear bodies (PODs) during maturation of RA-resistant t(15;17) promyelocytic leukemia NB4 cells expressing PML-RAR alpha.

We analysed the expression of retinoid receptors and PML in relation to the morphology of PML-containing nuclear bodies (PODs) in maturation sensitive (NB4) and resistant subclones (NB4-R1 and R2) of the promyelocytic NB4 cell line. The basal level of RARalpha, RXRalpha and PML mRNA and protein were roughly the same in the three cell lines. While NB4 and NB4-R1 cells express comparable amounts of PM-RARalpha mRNA and 120 kDa protein, NB4-R2 cells despite normal mRNA levels the 120 kDa protein was not detectable. In NB4-R2 cells however, two novel PML-related entities of 65 kDa and 85 kDA were detected with a anti-PML antibody, in addition to the two PML isoforms of 78 and 97 kDa found in any NB4 cells. Despite the 120 kDa PML-RARalpha defect, NB4-R2 cells show micropunctuated nuclear bodies typical of APL cells. Contrasting with NB4 cells, neither NB4-R1 cells which express PML-RARalpha, nor NB4-R2 cells lacking the 120 kDa PML-RARalpha reorganised nuclear bodies (PODs) in response to RA. Importantly, in RA-primed NB4-R1 cells, a secondary event triggered by cAMP restored PODs, concomitant to maturation. This indicates that the recovery of nuclear bodies in APL is dissociated from the early action of RA in cell maturation. Finally, the key finding of this work is that cAMP signalling ultimately determines the recovery of nuclear bodies associated to cell maturation.

Cell Cycle↗
PubMed1996

Establishment of a human acute promyelocytic leukemia-ascites model in SCID mice.

Acute promyelocytic leukemia (APL) is an interesting model for cancer research because of the presence of the specific PML-RARalpha fusion gene associated with the clinical response to retinoic acid differentiation therapy. To better understand and improve differentiation induction with retinoic acid, we have established a human APL-ascites model in SCID mice using the NB4 human APL cell line. NB4 (1 x 10(6) cells) were transplanted into the peritoneum (IP) of SCID mice for 1 month. NB4 ascites cells (A-NB4) appeared, which were then engrafted in SCID mice periodically for 18 passages at an interval of 3 to 4 weeks with a 100% success rate of tumor induction. The mean survival times of SCID mice transplanted with 1 x 10(6) A-NB4 cells was 21.6 +/- 2.3 days. Analysis of the biologic characteristics of ninth passage NB4 ascitic cells was performed and they were found to have the morphologic, immunologic, cytogenetic, and molecular features of cultured NB4 cells. Furthermore, A-NB4 cells were capable of differentiating when treated with all-trans retinoic acid (ATRA), as manifested by enhanced NBT reduction and CD11b expression. In vivo treatment with ATRA in SCID mice for 4 days also increased NBT reduction by A-NB4 cells. ATRA treatment significantly prolonged survival time in the group after transplantation (28.1 +/- 6.8 to 29.1 +/- 8.4 days) compared with the control (P < .001). Furthermore, treatment with adriamycin, an effective chemotherapeutic drug in APL, had a strong growth suppressive effect on A-NB4 cells. These results demonstrate that this SCID-APL (NB4 ascites cells) model is a useful preclinical system for evaluating new or known drugs in the treatment of APL.

Animals↗
PubMed1996

One hundred and twenty-seven cases of acute subdural haematoma operated on. Correlation between CT scan findings and outcome.

Traumatic acute subdural haematoma is one of the most lethal of all head injuries: the mortality rate is reported to be between 50 and 90%. We reviewed the clinical records of 1688 head injured patients admitted to the Department of Neurosurgery at C.T.O. hospital between 1982 and 1992. In 127 cases (7,5%) CTscan on admission showed acute subdural haematoma requiring surgery because the midline shift was greater than 5 mm. The overall mortality rate was 57% and 23% had functional recovery. The following variables were assessed with regard to morbidity and mortality: mechanism of injury, age, neurological presentation, time delay from injury to intervention, CTscan finding on admission. GCS and CTscan findings were found to be the most important prognostic variable. Timing of operative intervention for clot removal with regard to outcome was not statistically significant. But no conclusions regarding the importance of early haematoma evacuation can be drawn from such an oversimplifying statement, because it does not take into account factors like rapidity of haematoma development and related brain decompensation as well as additional direct brain lesions. The results of this study suggest that the extent of primary brain injury underlying the subdural haematoma is the most important factor affecting outcome.

Acute Disease↗
PubMed1995

Fine mapping of 28S rRNA sites specifically cleaved in cells undergoing apoptosis.

Bona fide apoptosis in rat and human leukemia cells, rat thymocytes, and bovine endothelial cells was accompanied by limited and specific cleavage of polysome-associated and monosome-associated 28S rRNA, with 18S rRNA being spared. Specific 28S rRNA cleavage was observed in all instances of apoptotic death accompanied by internucleosomal DNA fragmentation, with cleavage of 28S rRNA and of DNA being linked temporally. This indicates that 28S rRNA fragmentation may be as general a feature of apoptosis as internucleosomal DNA fragmentation and that concerted specific cleavage of intra- and extranuclear polynucleotides occurs in apoptosis. Apoptosis-associated cleavage sites were mapped to the 28S rRNA divergent domains D2, D6 (endothelial cells), and D8. The D2 cuts occurred in hairpin loop junctions considered to be buried in the intact ribosome, suggesting that this rRNA region becomes a target for RNase attack in apoptotic cells. D8 was cleaved in two exposed UU(U) sequences in bulge loops. Treatment with agents causing necrotic cell death or aging of cell lysates failed to produce any detectable limited D2 cleavage but did produce a more generalized cleavage in the D8 region. Of potential functional interest was the finding that the primary cuts in D2 exactly flanked a 0.3-kb hypervariable subdomain (D2c), allowing excision of the latter. The implication of hypervariable rRNA domains in apoptosis represents the first association of any functional process with these enigmatic parts of the ribosomes.

Animals↗
PubMed1995

Distinct apoptotic responses in maturation sensitive and resistant t(15;17) acute promyelocytic leukemia NB4 cells. 9-cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression.

Apoptosis has been investigated in NB4, a t(15;17) human promyelocytic leukemia cell line susceptible to maturation by all-trans or 9-cis retinoic acid, and in NB4-R1, a subclone resistant to differentiation. Maturation resistant NB4-R1 cells exhibited an onset of cell death after RA-treatment (72 h), whereas maturation responsive NB4 cells showed no such apoptosis, cell death being considerably delayed after cell maturation. Only a few NB4-R1 cells underwent apoptosis in response to low doses of RA (below 0.1 microM), the surviving cells became refractory to higher doses of RA. While these cells became 'resistant' to apoptosis they became competent for maturation. Typically, these RA-'primed' cells responded to cAMP by maturation, then apoptosis followed rapidly. This model furnishes situations where cells are either resistant or susceptible to apoptosis, depending on whether they can or cannot undergo maturation. The potential role of the Bcl-2 protein in the regulation of apoptosis was analyzed. In NB4 and NB4-R1 cell lines, a high expression of the Bcl-2 protein was detected by immunocytology and Western blotting. NB4 cells treated with either all-trans or 9-cis retinoic acid (1 microM) were induced to differentiate and the level of Bcl-2 protein decreased to undetectable levels during terminal maturation when only a few apoptotic cells were detected. In NB4-R1 cells, while treatment with retinoids does not induce maturation, as much as 64% of cells became apoptotic, and immunocytological labelling of NB4-R1 showed a strong cytoplasmic labelling of Bcl-2. Although the expression of Bcl-2 remained high, cells were not protected from apoptosis. To assess whether Bcl-2 expression could be modulated as a consequence of differentiation, NB4-R1 cells previously 'primed' for maturation were triggered with cAMP. Downregulation of Bcl-2 protein occurred concomitant with maturation, followed by apoptosis. Clearly, NB4 and NB4-R1 cells show reciprocal behavior with regards to proliferation, maturation, Bcl-2 regulation and apoptosis in response to RA. Our results suggest, first, that the Bcl-2 downregulation in NB4 cells belongs to the maturation program rather than to apoptosis, and second, that neither a high Bcl-2 expression in NB4 cells is sufficient to protect cells from 9-cis RA induced apoptosis, nor is its full downregulation sufficient to produce apoptosis. Finally, this work suggests that apoptosis and maturation programs include events which cannot occur simultaneously.

Apoptosis↗
PubMed1994

Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line.

In t(15;17) acute promyelocytic leukemia, all-trans retinoic acid (RA) induces leukemic cell maturation in vitro and remission in acute promyelocytic leukemia patients, but in vivo treatments invariably lead to relapse with resistance to RA. NB4, a maturation-inducible cell line, and NB4-RAr sublines (R1 and R2) displaying no maturation in the presence of RA have been isolated from a patient in relapse. We show that resistance to maturation is not a mere unresponsiveness to RA: rather, R1 "resistant" cells do respond to RA (1 microM) by sustained growth, become competent to undergo terminal maturation, and up-regulate CD11c/CD18 integrins. Interestingly, maturation of "resistant" cells, rendered competent by RA, can be achieved by cAMP-elevating agents (prostaglandin E, isoproterenol, cholera toxin, or phosphodiesterase inhibitor) or stable agonistic cAMP analogs such as (SP)-8-chloroadenosine cyclic 3',5'-phosphorothioate. This shows that activation of cAMP-dependent protein kinase (cA kinase) can override the RA resistance and suggests interdependent RA and cAMP signaling pathways in acute promyelocytic leukemia maturation. No such cooperation was observed in the R2 resistant cells, though their cA-kinase was functional. (RP)-8-Chloroadenosine cyclic 3',5'-phosphorothioate, which by displacing endogenous cAMP inhibits the basal cA-kinase activity, decreased the response of sensitive cells to RA. This raises the possibility that cA-kinase plays a key role in the maturation also of RA-sensitive cells. Our results define two discrete steps in the maturation process: an RA-dependent priming step that maintains proliferation while cells become competent to undergo maturation in response to retinoids and a cAMP-dependent step that triggers RA-primed cells to undergo terminal maturation. Uncoupling RA and cAMP action might cause the so-called "resistance."

Antigens, CD↗
PubMed1994

The phylogeny of proteinase 3/myeloblastin, the autoantigen in Wegener's granulomatosis, and myeloperoxidase as shown by immunohistochemical studies on human leukemic cell lines.

Proteinase 3/myeloblastin (Pr3/MBN) is a serine protease found in primary granules of neutrophilic granulocytes and monocytes in man. This enzyme has been identified as the main autoantigen in Wegener's granulomatosis. Pr3/MBN was earlier identified in the promyelocytic cell line HL-60 and was assumed to be at least partly responsible for controlling proliferation and differentiation within the granulocytic-monocytic system. We have investigated 98 leukemic cell lines representing all lineages of the hemopoietic system. Pr3/MBN was found to appear in mature myeloblastic precursors and in CD34+ immature monoblastic cells and was restricted to the granulocytic and monocytic lineage. Myeloperoxidase (MPO) was found to be expressed earlier in development in the granulocytic lineage, but appeared later than Pr3/MBN in the monocytic lineage. The identification of cell lines which contained Pr3 only or MPO only may make them useful for demonstration of anti-neutrophil cytoplasmic antibodies in primary vasculitides.

Autoantigens↗
PubMed1994

Intracisternal schwannoma of the spinal accessory nerve presenting as a normal pressure hydrocephalus syndrome. Case report and review of the literature.

Schwannomas of the spinal accessory nerve are rare lesions. They can be characterized by their locations as either intrajugular or intracisternal schwannomas, most of them being intrajugular. Only five cases arising in the cisterna magna are reported in literature. Clinical symptoms generally consist of 11th cranial nerve palsy associated with cerebellar signs and myelopathy. An additional case, studied by MRI, is described. The patient showed a mild cerebellar syndrome and normal pressure hydrocephalus symptoms. He was operated on and the mass completely removed with good postoperative results. The role of MRI for diagnosis of lower cranial nerve schwannomas is stressed, even though does not detect the exact nerve of origin. Total removal of these lesions is recommended, since their benign nature and unavoidable recurrence in case of partial excision.

Accessory Nerve↗